UGT1A1 Genotyping - Irinotecan

Diagnosis

Indications for Testing

  • Patient who will receive irinotecan (in doses >150 mg/m2), who has a history of irinotecan sensitivity, or who experiences neutropenia while receiving irinotecan
  • Patient suspected to have Gilbert syndrome

Laboratory Testing

  • UGT1A1 (TA) polymorphism test
    • Risk of irinotecan toxicity by genotype

      Risk of irinotecan toxicity by genotype*

      TA genotype

      Diarrhea risk

      Neutropenia risk

      6/6 (*1/*1)

      18%

      10%

      6/7 (*1/*28)

      27%

      23%

      7/7 (*28/*28)

      27%

      92%

  • UGT1A1 genotype does not significantly influence risk of irinotecan toxicity when low dose therapy with irinotecan (eg, 15-75 mg/m2 daily for five days for two consecutive weeks) is employed

Clinical Background

Irinotecan (CPT-11) is a common chemotherapeutic drug used for the treatment of advanced colorectal and gastric cancer. Allelic variance of UGT1A1 may be associated with increased drug toxicity and with syndromes such as Gilbert syndrome (benign familial hyperbilirubinemia) and Crigler-Najjar (rare form of nonhemolytic jaundice).

Epidemiology

  • Prelavence

(TA)

Caucasian

Asian

African American

6

61%

84%

47%

7

39%

16%

43%

Genetics

  • The polymorphic TA repeat in the TATA element of the 5’-promoter region of UGT1A1 may consist of 5, 6, 7, or 8 repeats [(TA)5, (TA)6, (TA)7, (TA)8]
    • (TA)6 (also known as UGT1A1*1)  – most common number of repeats
    • (TA)7 (also known as UGT1A1*28)  – important genotype for risk of severe drug-induced toxicity
      • Increase in number of TA repeats may reduce transcription efficiency, lower enzyme concentrations, and lead to accumulation of SN-38 and risk for toxicities
    • (TA)5 and (TA)8 alleles are rare but may also be clinically significant
      • Number of TA repeats thought to be inversely related to expression of UGT1A1 protein, such that (TA)8 would be associated with the most impaired transcription efficiency

Pathophysiology

  • UGT1A1 is responsible for the clearance, by glucuronidation, of drugs (eg, irinotecan) and endogenous substances (eg, bilirubin)
    • >150 functional polymorphisms on UGT1A1 locus
  • SN-38 – primary active and toxic metabolite of irinotecan
    • SN-38 is inactivated by UGT1A1 to form SN-38G, which is eliminated via bile
  • Variations of the TA repeat length in the UGT1A1 promoter TATA element may lead to decreased gene expression, accumulation of SN-38, and irinotecan-related toxicities
    • Variations of the TA region are associated with Gilbert syndrome
  • Presence of UGT1A1*28 also may affect treatment with the following agents
    • Raloxifene
    • Raltegravir
    • Indinavir
    • Atazanavir
    • Sorafenib

Clinical Presentation

  • Irinotecan toxicity-related symptoms
    • Typically severe (grade 3/4) diarrhea and neutropenia
  • Other related symptoms
    • Nausea, fever, alopecia

Indications for Laboratory Testing

  • Tests generally appear in the order most useful for common clinical situations
  • Click on number for test-specific information in the ARUP Laboratory Test Directory
Test Name and Number Recommended Use Limitations Follow Up
UDP Glucuronosyltransferase 1A1 (UGT1A1) Genotyping 0051332
Method: Polymerase Chain Reaction/Fragment Analysis

Dosage planning for individuals

  • Who will receive high-dose irinotecan (>150 mg/m2)
  • With personal or family history of sensitivity to irinotecan
  • Who have experienced neutropenia while receiving irinotecan

Confirm suspected diagnosis of Gilbert syndrome

Clinical significance if (TA)5 and (TA)8 is not well-established

Other variants such as those associated with Crigler-Najjar syndrome will not be detected

(TA)5 and (TA)8 are not detected

Other factors that contribute to irinotecan toxicity will not be detected